Vasc Demlecture

Vascular Dementia Vascular Dementia

Moises Gaviria MDDistinguished Professor of Psychiatry University of Illinois at Chicago

Director of Neuropsychiatry at Christ /Advocate Medical Center

Moises Gaviria MDDistinguished Professor of Psychiatry University of Illinois at Chicago

Director of Neuropsychiatry at Christ /Advocate Medical Center

HISTORICALHISTORICAL PERSPECTIVEPERSPECTIVEHISTORICALHISTORICAL PERSPECTIVEPERSPECTIVE

Historical OverviewHistorical OverviewPerhaps the earliest clinical description ofvascular dementia comes from ThomasWillis, whose careful attention to the cerebral vasculature led to his description of the circle of Willis in 1684.Under the heading “A palsie often succeeds stupidity, or becoming foolish,” he relates the following:

I have observed in many, that when, the Brainbeing first indisposed, they have beendistempered with a dullness of mind, and forgetfulness, and afterwards with a stupidityand foolishness, after that, have fallen into apalsie, which I often did predict.

Perhaps the earliest clinical description ofvascular dementia comes from ThomasWillis, whose careful attention to the cerebral vasculature led to his description of the circle of Willis in 1684.Under the heading “A palsie often succeeds stupidity, or becoming foolish,” he relates the following:

I have observed in many, that when, the Brainbeing first indisposed, they have beendistempered with a dullness of mind, and forgetfulness, and afterwards with a stupidityand foolishness, after that, have fallen into apalsie, which I often did predict.

Historical Overview Historical Overview

proposed a concept of “arteriosclerotic brain degeneration”proposed a concept of “arteriosclerotic brain degeneration”

Binswanger (1894) Binswanger (1894)

Historical Overview Historical OverviewOtto Binswanger and Alois Alzheimer

separated the dementia paralytica

(neurosyphilis), a common disease

at that time, from vascular dementia

Based on this classification Kraepelin

concluded that cerebral arteriosclerosis or

arteriosclerotic insanity was the most

frequent form of senile dementia

Otto Binswanger and Alois Alzheimer

separated the dementia paralytica

(neurosyphilis), a common disease

at that time, from vascular dementia

Based on this classification Kraepelin

concluded that cerebral arteriosclerosis or

arteriosclerotic insanity was the most

frequent form of senile dementia

Emil Kraeplin (1856-1926)Emil Kraeplin (1856-1926)

Historical OverviewHistorical Overview

DSM-II (1968), the term “arteriosclerotic brain degeneration” was modified to “ psychosis with cerebral arteriosclerosis “

DSM-II (1968), the term “arteriosclerotic brain degeneration” was modified to “ psychosis with cerebral arteriosclerosis “

Hachinski (1974) proposed the term multi-infarct dementia (MID), and the original Hachinski Ischemic Score (HIS) providing criteria for diagnosis of vascular dementia.

Hachinski (1974) proposed the term multi-infarct dementia (MID), and the original Hachinski Ischemic Score (HIS) providing criteria for diagnosis of vascular dementia.

In 1991 Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of vascular dementia

In 1991 Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of vascular dementia

Historical OverviewHistorical Overview

Neurology 1993; 43: 250-260

VaD ClassificationsVaD ClassificationsAll existing classifications identify patients with VaD, but their sensitivity and specificity vary.

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV],

National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences [NINDS-AIREN],

International Statistical Classification of Diseases, 10th Revision [ICD-10]

California Alzheimer’s Disease Diagnostic and Treatment Centers [CAD-DTC]

All existing classifications identify patients with VaD, but their sensitivity and specificity vary.

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV],

National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences [NINDS-AIREN],

International Statistical Classification of Diseases, 10th Revision [ICD-10]

California Alzheimer’s Disease Diagnostic and Treatment Centers [CAD-DTC]

VaD ClassificationsVaD Classifications

The criteria of the CAD-DTC apply exclusively to VaD caused by ischemic CVD

NINDS-AIREN criteria recognize that VaD may result from complete or incomplete brain ischemia, cerebral hemorrhage, and other vascular or circulatory injuries to the brain.

Both evolved from the Hachinski Ischemic Scale [HIS].

Both sets of VaD criteria rely on neuroimaging by CT or MRI for confirmation of cerebrovascular lesions .

Lesions include both large and small vessel ischemia.

The criteria of the CAD-DTC apply exclusively to VaD caused by ischemic CVD

NINDS-AIREN criteria recognize that VaD may result from complete or incomplete brain ischemia, cerebral hemorrhage, and other vascular or circulatory injuries to the brain.

Both evolved from the Hachinski Ischemic Scale [HIS].

Both sets of VaD criteria rely on neuroimaging by CT or MRI for confirmation of cerebrovascular lesions .

Lesions include both large and small vessel ischemia.

Erkinjuntti, Timo MD; Roman, Gustavo et al. Emerging Therapies for Vascular Dementia and Vascular Cognitive Impairment.

Stroke. 35(4):1010-1017, April 2004.


Stroke. 35(4):1010-1017, April 2004.

Large-vessel injuries are:

Multiple either cortical or cortico-subcortical infarcts

Single, strategically placed infarcts that occur in areas that are crucial for cognition or behavior

Angular gyrus

Basal forebrain

Thalamus

Anterior or posterior cerebral artery strokes

Small-vessel injury is manifested as:

Multiple basal ganglia and white matter lacunae

Extensive white matter lesions

Combinations of both.

Patients can have evidence of either large-vessel or small-vessel disease or both.

Large-vessel injuries are:

Multiple either cortical or cortico-subcortical infarcts

Single, strategically placed infarcts that occur in areas that are crucial for cognition or behavior

Angular gyrus

Basal forebrain

Thalamus

Anterior or posterior cerebral artery strokes

Small-vessel injury is manifested as:

Multiple basal ganglia and white matter lacunae

Extensive white matter lesions

Combinations of both.

Patients can have evidence of either large-vessel or small-vessel disease or both.


Stroke. 35(4):1010-1017, April 2004.


Stroke. 35(4):1010-1017, April 2004.


The NINDS-AIREN criteria are currently most widely used in clinical drug trials on VaD.

Based on neuropathological series

sensitivity was 58%,

specificity was 80%,

successfully excluded AD in 91% of cases,

proportion of combined cases misclassified as probable VaD was 29%.

Compared to the CADDTC criteria, the NINDS-AIREN criteria were more specific, and they better excluded combined cases (54% vs. 29%)

The NINDS-AIREN criteria are currently most widely used in clinical drug trials on VaD.

Based on neuropathological series

sensitivity was 58%,

specificity was 80%,

successfully excluded AD in 91% of cases,

proportion of combined cases misclassified as probable VaD was 29%.

Compared to the CADDTC criteria, the NINDS-AIREN criteria were more specific, and they better excluded combined cases (54% vs. 29%)

Gold, G., P. et al.. Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia. Neurology 49 1997, : 690-694Gold, G., P. et al.. Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia. Neurology 49 1997, : 690-694


PATHOGENESISPATHOGENESISPATHOGENESISPATHOGENESIS

Pathogenetic mechanismsPathogenetic mechanisms

Regional cerebral blood flow is reduced

Oxidative stress including free radicals

Damage of endothelial cells

Chronic hypoperfusion

Polioararoisis and leukoaroiosis

Changes in the small penetrating arteries and arterioles in the white matter

Regional cerebral blood flow is reduced

Oxidative stress including free radicals

Damage of endothelial cells

Chronic hypoperfusion

Polioararoisis and leukoaroiosis

Changes in the small penetrating arteries and arterioles in the white matter

A

PEC

NORMAL CAPILLARY

A

P

EC

SVaD CAPILLARYBL BL

L

L

A= astrocyte

P=perycite

EC= endothelial cell

BL= basal lamina

L=lumen

Thickened basal lamina Endothelial cell shape distorsion Degenerating perycite Severe luminal blocking

NFkbNFkb

iNOS receptoriNOS receptor

Regulation protein transcriptonRegulation protein transcripton

IkBaIkBa

eNOSeNOS

EndotheliumEndotheliumEndotheliumEndothelium Endothelial changesEndothelial changes Cytokines activationCytokines activation

NONO

H2O2H2O2

O-2O-2

NONOO-2O-2

H2O2H2O2

H2O2H2O2

•Citosolic Superoxide Dysmutase•Citosolic Superoxide Dysmutase

endotheliumendothelium

PPARjPPARjCuZn-SODCuZn-SODNFkbNFkb

Angiotensin II receptorAngiotensin II receptor

ANGIOTENSIN IIANGIOTENSIN II

KidneyKidneyArteriolar vasoconstrictionArteriolar vasoconstriction

INCREASED BLOOD PRESSUREINCREASED BLOOD PRESSURE

Peroxisome Proligerator Activated ReceptorPeroxisome Proligerator Activated Receptor

CuZn Superoxide DysmutaseCuZn Superoxide Dysmutase

IMAGINGIMAGINGIN IN

VaDVaD

IMAGINGIMAGINGIN IN

VaDVaD

Increased sophistication of imaging in VaD


Initially CT scanning demonstrated lacunar infarcts as well as patches of white matter disease (leukoariosis).

Then the MRI scan, particularly with the fluid-attenuated inversion recovery (FLAIR) sequences dramatically demonstrated not only the extent of the white matter disease, the hallmark of small vessel disease, but also the small cortical lesions that were not identified on the old T1 and T2 sequences.

In addition to localizing lesions in the brain, it is now possible to quantitate the extent of the white matter change using an automated magnetic resonance tissue class segmentation technique.

Initially CT scanning demonstrated lacunar infarcts as well as patches of white matter disease (leukoariosis).

Then the MRI scan, particularly with the fluid-attenuated inversion recovery (FLAIR) sequences dramatically demonstrated not only the extent of the white matter disease, the hallmark of small vessel disease, but also the small cortical lesions that were not identified on the old T1 and T2 sequences.

In addition to localizing lesions in the brain, it is now possible to quantitate the extent of the white matter change using an automated magnetic resonance tissue class segmentation technique.

Wei X, et al. Quantitative analysis of MRI white matter signal abnormalities with high reproducibility and accuracy. J Magn Reson Imaging 2002; 15: 203–209Wei X, et al. Quantitative analysis of MRI white matter signal abnormalities with high reproducibility and accuracy. J Magn Reson Imaging 2002; 15: 203–209

In addition to the morphologic imaging techniques, functional scans; PET and SPECT are able to image perfusion and, in the case of PET, oxygen or glucose use of the cortical gray and subcortical white matter tissue.

This is useful in differentiating VaD from Alzheimer's disease, where there is a temporal and parietal decrease in uptake, from the scattered perfusion defects seen in vascular dementia.

In addition to the morphologic imaging techniques, functional scans; PET and SPECT are able to image perfusion and, in the case of PET, oxygen or glucose use of the cortical gray and subcortical white matter tissue.

This is useful in differentiating VaD from Alzheimer's disease, where there is a temporal and parietal decrease in uptake, from the scattered perfusion defects seen in vascular dementia.



MRI Procedures with Clinical Significance

MRI Procedures with Clinical Significance

Diffussion and perfusion MRI are being used increasingly in neurovascular clinical applications.

DTI is being found to be a helpful technique in the studies of the white matter disease and in correlating it with cognitive impairment

Diffussion and perfusion MRI are being used increasingly in neurovascular clinical applications.

DTI is being found to be a helpful technique in the studies of the white matter disease and in correlating it with cognitive impairment

Anisotropy in White MatterAnisotropy in White Matter

Isotropic diffusion.No barriers to motion of hydrogen

Diffusion in CSF Diffusion in White Matter

Anisotropic diffusion.Hydrogen flows along the axis of

the white matter tract

Fractional Anisotropy = 0.05 FA = 0.75

Myelinbarrier

Courtesy of G. Stebbins

Diffusion Tensor ImagingDiffusion Tensor Imaging

White matter hyperintensitiesWhite matter hyperintensities

White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted and fluid-attenuated inversion recovery MRI sequences of the brain. These phenomena may not be benign because they are seen in up to 70% of persons with vascular dementia and Alzheimer’s disease.

White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted and fluid-attenuated inversion recovery MRI sequences of the brain. These phenomena may not be benign because they are seen in up to 70% of persons with vascular dementia and Alzheimer’s disease.

Stroke Risk Profile Predicts White Matter Hyperintensity Volume The Framingham Study Tom Jeerakathil et al. (Stroke. 2004;35:1857-1861.)


Multiple studies have found adverse associations between WMH and neuropsychological function, gait and balance, lower extremity function, depression, and recurrent stroke and death.

Multiple studies have found adverse associations between WMH and neuropsychological function, gait and balance, lower extremity function, depression, and recurrent stroke and death.




Stroke Risk Profile Predicts White MatterHyperintensity Volume


Offspring subjects obtained from the Framingham Cohort were invited to undergo a brain MRI using a standard protocol to assess the relationship between WMHV and 10 year probability of stroke events.

The contribution of individual risk factors to the 10-year probability of stroke events was determined using sex-specific Cox proportional hazard models.

Offspring subjects obtained from the Framingham Cohort were invited to undergo a brain MRI using a standard protocol to assess the relationship between WMHV and 10 year probability of stroke events.

The contribution of individual risk factors to the 10-year probability of stroke events was determined using sex-specific Cox proportional hazard models.





Component risk factors included: Age in years Systolic blood pressure (SBP) in mm Hg Use of antihypertensive medication Diabetes Number of cigarettes smoked per day CVD Atrial fibrillation Left ventricular hypertrophy (LVH) by electrocardiogram (EKG).

Component risk factors included: Age in years Systolic blood pressure (SBP) in mm Hg Use of antihypertensive medication Diabetes Number of cigarettes smoked per day CVD Atrial fibrillation Left ventricular hypertrophy (LVH) by electrocardiogram (EKG).



MRI study in elderly peopleMRI study in elderly people

If the MRI findings are markers for early cognitive and gait impairments, identification and control of causal factors could reduce the risk of these common problems of the elderly.

If the MRI findings are markers for early cognitive and gait impairments, identification and control of causal factors could reduce the risk of these common problems of the elderly.

WT Lonstreth, Teri Manolio, Alice Arnold et al. Clinical correlates of White Matter Findings on Cranial Magnetic Resonance Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282



Correlates of white matter findings were sought among 3301 elderly people who underwent MRI scanning and denied history of stroke or transient ischemic attacks.

Participants underwent extensive standardized evaluations at baseline and on follow up, including standard questionnaires, physical examination, multiple blood tests, ECG, PFT’s etc.

Correlates of white matter findings were sought among 3301 elderly people who underwent MRI scanning and denied history of stroke or transient ischemic attacks.

Participants underwent extensive standardized evaluations at baseline and on follow up, including standard questionnaires, physical examination, multiple blood tests, ECG, PFT’s etc.




Many potential risk were related to the white matter grade, but in the multivariate model the factors significantly (all P< .01) and independently associated with increased grade were:

Greater ageClinically silent stroke on MRIHigher systolic blood pressureLower forced expiratory volume in 1 second (FEV1) Income less than $ 50,000 per year

Many potential risk were related to the white matter grade, but in the multivariate model the factors significantly (all P< .01) and independently associated with increased grade were:

Greater ageClinically silent stroke on MRIHigher systolic blood pressureLower forced expiratory volume in 1 second (FEV1) Income less than $ 50,000 per year



Descriptive term introduced in 1987 by Hachinski and colleagues to indicate the periventricular white matter

MR hyperintensities frequently found in elderly people

Descriptive term introduced in 1987 by Hachinski and colleagues to indicate the periventricular white matter

MR hyperintensities frequently found in elderly people

LeukoaraiosisLeukoaraiosis

LeukaraiosisLeukaraiosis

Demyelinization in brain subcortical structures

Loss of glia cells

Spongy appearance and occlusion of veins and venules by collagenous thickening of vessels walls

Changes in the small penetrating arteriolae in the white matter

Leukoaraiosis could be graded

Demyelinization in brain subcortical structures

Loss of glia cells

Spongy appearance and occlusion of veins and venules by collagenous thickening of vessels walls

Changes in the small penetrating arteriolae in the white matter

Leukoaraiosis could be graded

Diagnosis of Acute Stroke Diagnosis of Acute Stroke 65 y.o. male Hx HTN, c/o feeling of LE weakness 65 y.o. male Hx HTN, c/o feeling of LE weakness

Courtesy of K. Thoulborn

Diagnosis: Early Subacute StrokeDiagnosis: Early Subacute Stroke

65 y.o. male Hx HTN, c/o feeling of weakness 65 y.o. male Hx HTN, c/o feeling of weakness

DWI

ADC


High Risk PatientsHigh Risk Patients Patient s/p stroke and occlusion of left

ICA Patient s/p stroke and occlusion of left

ICA

Pre Gd post Gd

FLAIR GRE DTI (FA)

Left ICA Occlusion


Perfusion for Hemodynamic ReservePerfusion for Hemodynamic Reserve

1 10 20 30 40

8000

6000

4000

2000

0

Vasodilation (acetozolamide)

1 10 20 30 40

8000

6000

4000

2000

0


Tissue PerfusionTissue Perfusion

Relative CBV Tissue Transit Time


Hemodynamic Reserve Hemodynamic Reserve

Hand Clasping Paradigm fMRI - cognitive stress test for hemodynamic reserve

17 -17

4.0 -4.0


Diffusion-weighted MRI for the details

of acute cerebral ischemia

Diffusion-weighted MRI for the details

of acute cerebral ischemia

DWI in strokeDWI in stroke

DWI in VaDDWI in VaD

Diffusion-weighted MRI (DWI) has already had a substantial affect on the diagnosis of patients with ischemic stroke. It provides in vivo pathological information and allows the differentiation of acute stroke from chronic stroke and from non-specific white matter lesions.

Diffusion-weighted MRI (DWI) has already had a substantial affect on the diagnosis of patients with ischemic stroke. It provides in vivo pathological information and allows the differentiation of acute stroke from chronic stroke and from non-specific white matter lesions.Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.

The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45)

Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.

The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45)


The high contrast of the acute DWI lesion against the dark background facilitates the detection of lesions even when they are 1mm or less in diameter.

The high contrast of the acute DWI lesion against the dark background facilitates the detection of lesions even when they are 1mm or less in diameter.


The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45




Small lesions. Which are undetectable by other means, include small lacunar infarcts, punctate cortical infarcts, and DWI bright dots in patients with transient ischemic attacks (TIA). The latter constitute remnants or “footprints” of recent ischemia and confirm the clinical TIA syndrome as ischemic.

Small lesions. Which are undetectable by other means, include small lacunar infarcts, punctate cortical infarcts, and DWI bright dots in patients with transient ischemic attacks (TIA). The latter constitute remnants or “footprints” of recent ischemia and confirm the clinical TIA syndrome as ischemic.

Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz. The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz. The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45


Because of these attributes, DWI not only confirms the clinical diagnosis, but also facilitates the recognition of certain patterns of ischemia, thereby providing clues to the underlying aetiology. DWI is becoming an important technique for optimum management of patients.

Because of these attributes, DWI not only confirms the clinical diagnosis, but also facilitates the recognition of certain patterns of ischemia, thereby providing clues to the underlying aetiology. DWI is becoming an important technique for optimum management of patients.Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.





Gerraty and colleagues confirmed that infarct pathogenesis can be better revealed with DWI than with conventional MRI in patients with lacunar stroke syndromes. They used DWI and perfusion-weighted MRI (PWI) within 24 hrs. of stroke in a prospective series of 106 patients, including 19 with lacunar syndrome. With use of DWI and PWI, the final diagnosis of infarct pathogenesis was changed from occlusion of small perforating artery to large-artery embolism in 13 of the 19 patients who presented with lacunar syndromes.

Gerraty and colleagues confirmed that infarct pathogenesis can be better revealed with DWI than with conventional MRI in patients with lacunar stroke syndromes. They used DWI and perfusion-weighted MRI (PWI) within 24 hrs. of stroke in a prospective series of 106 patients, including 19 with lacunar syndrome. With use of DWI and PWI, the final diagnosis of infarct pathogenesis was changed from occlusion of small perforating artery to large-artery embolism in 13 of the 19 patients who presented with lacunar syndromes.

Oliveira-Filho j, Ay Koroshetz WJ, et al. Localization of clinical syndromes using DWI: two examples of the “capsular” warning syndrome. J Neuroimaging 2001; 11: 44-47

Oliveira-Filho j, Ay Koroshetz WJ, et al. Localization of clinical syndromes using DWI: two examples of the “capsular” warning syndrome. J Neuroimaging 2001; 11: 44-47

Hypertension and VaDHypertension and VaD


Dementia and a decline in cognitive function have been added to the consequences of hypertension.

Dementia and a decline in cognitive function have been added to the consequences of hypertension.




Hypertension is an established risk factor both for stroke and coronary heart disease. And the fact that the prevalence of hypertension increase with age provides one explanation for the expected rise in stroke and coronary heart morbidity in the future as the population in industrialized countries ages.

Hypertension is an established risk factor both for stroke and coronary heart disease. And the fact that the prevalence of hypertension increase with age provides one explanation for the expected rise in stroke and coronary heart morbidity in the future as the population in industrialized countries ages.




The SCOPE trial was initiated as a placebo-controlled study with the aim of assessing the effects of antihypertensive treatment with the angiotensin II type 1 (AT 1) receptor blocker candesartan cilexetil (canderartan) in elderly (70-89 years) patients with SBP 160-179mmHg and /or diastolic blood pressure (DBP) 90-99mmHg.

The SCOPE trial was initiated as a placebo-controlled study with the aim of assessing the effects of antihypertensive treatment with the angiotensin II type 1 (AT 1) receptor blocker candesartan cilexetil (canderartan) in elderly (70-89 years) patients with SBP 160-179mmHg and /or diastolic blood pressure (DBP) 90-99mmHg.




The benefits of antihypertensive treatment in the elderly are well established.

Several large intervention trials have shown a significant reduction in the incidence of stroke and cardiovascular morbidity in treated elderly with hypertension.

The benefits of antihypertensive treatment in the elderly are well established.

Several large intervention trials have shown a significant reduction in the incidence of stroke and cardiovascular morbidity in treated elderly with hypertension.



Because changed in the treatment guidelines and for ethical reasons it became necessary during the recruitment period to recommend open-label active antihypertensive therapy in both treatment groups for patients whose blood pressure remained high.

As a result, the trial actually compared a candesartan-based regimen with a usual treatment not containing candersartan.

Because changed in the treatment guidelines and for ethical reasons it became necessary during the recruitment period to recommend open-label active antihypertensive therapy in both treatment groups for patients whose blood pressure remained high.

As a result, the trial actually compared a candesartan-based regimen with a usual treatment not containing candersartan.



Treatment Treatment OptionsOptions

Treatment Treatment OptionsOptions

Treatment of VaDTreatment of VaD

Primary and secondary stroke prevention

can decrease VaD incidence.

Treatment can be divided in:

improvement of core symptoms (cognition, function and behavior)

slowing progression

neuropsychiatric symptoms (depression, agitation, anxiety)

Primary and secondary stroke prevention

can decrease VaD incidence.

Treatment can be divided in:

improvement of core symptoms (cognition, function and behavior)

slowing progression

neuropsychiatric symptoms (depression, agitation, anxiety)

Primary preventionPrimary prevention

Treatment of vascular risk factors (HTN, lipid abnormalities, atrial fibrillation, MI, CAD, DM, smoking, hyperhomocysteinemia)

Treatment of isolated systolic HTN in elderly decreased incidence of dementia significantly

Treatment of vascular risk factors (HTN, lipid abnormalities, atrial fibrillation, MI, CAD, DM, smoking, hyperhomocysteinemia)

Treatment of isolated systolic HTN in elderly decreased incidence of dementia significantly

Forette et al “ The prevention of dementia with antihypertensive treatmentNew evidence from the Systolic Hypertentsion in Europe”Arch Int Med 162, 2002

Forette et al “ The prevention of dementia with antihypertensive treatmentNew evidence from the Systolic Hypertentsion in Europe”Arch Int Med 162, 2002

Secondary preventionSecondary prevention

Early diagnosis and treatment of acute stroke.

Prevention of stroke recurance: Statins shown to prevent dementia in animal studies

Perindopril (ACE inhibitor) showed strikingly beneficial effects in reducing the risk of dementia and cognitive impairment in pts with recurrent stroke

Early diagnosis and treatment of acute stroke.

Prevention of stroke recurance: Statins shown to prevent dementia in animal studies

Perindopril (ACE inhibitor) showed strikingly beneficial effects in reducing the risk of dementia and cognitive impairment in pts with recurrent stroke

Fassbender et al Proc. Natl. Acad.Sci. 2001

The PROGRESS collaborative group Arch. Int. Med. 2003 Fassbender et al Proc. Natl. Acad.Sci. 2001

The PROGRESS collaborative group Arch. Int. Med. 2003

Secondary prevention cont’d.Secondary prevention cont’d.

Intensive management of existing risk factors

Fasting total homocysteine is an independent predictor of cognitive declineElevated homocysteine is a marker of folate/B12 deficiencySignificant improvement in cognition shown after supplementation in pts with mild to moderate dementia

Intensive management of existing risk factors

Fasting total homocysteine is an independent predictor of cognitive declineElevated homocysteine is a marker of folate/B12 deficiencySignificant improvement in cognition shown after supplementation in pts with mild to moderate dementia

Nilsson et al. “Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine.” International Journal of Geriatric Psychiatry. 2001.

Nilsson et al. “Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine.” International Journal of Geriatric Psychiatry. 2001.

Numerous compounds purported to be useful in the symptomatic treatment of VaD include:

AntithromboticsErgot alkaloidsNootropicsThyrotropin-releasing hormone analogueGinkgo biloba extractsPlasma viscosity drugsHyperbaric oxygenAntioxidantsCalcium antagonists.

These studies had mostly negative results, were based on small numbers and short treatment periods, and often included mixed populations and various diagnostic criteria, evaluation tools, and clinical end points.

Numerous compounds purported to be useful in the symptomatic treatment of VaD include:

AntithromboticsErgot alkaloidsNootropicsThyrotropin-releasing hormone analogueGinkgo biloba extractsPlasma viscosity drugsHyperbaric oxygenAntioxidantsCalcium antagonists.

These studies had mostly negative results, were based on small numbers and short treatment periods, and often included mixed populations and various diagnostic criteria, evaluation tools, and clinical end points.

Pharmacotherapy of of VaDPharmacotherapy of of VaD

Erkinjuntti, Timo MD; Román, Gustavo MD et al. Emerging Therapies for Vascular Dementia and Vascular Cognitive Impairment Lancet 35(4) April 2004 1010-1017Erkinjuntti, Timo MD; Román, Gustavo MD et al. Emerging Therapies for Vascular Dementia and Vascular Cognitive Impairment Lancet 35(4) April 2004 1010-1017

Pharmacotherapy of of VaDPharmacotherapy of of VaD

Cholinergic deficits are well documented in VaD, independently of any concomitant AD pathology. Cholinergic structures are vulnerable to ischemic damage; for instance, basal forebrain cholinergic nuclei are irrigated by penetrating arterioles susceptible to the effects of arterial hypertensionHippocampal CA1 neurons are particularly vulnerable to experimental ischemia, and hippocampal atrophy is common in patients with VaD in the absence of AD.

Cholinergic deficits are well documented in VaD, independently of any concomitant AD pathology. Cholinergic structures are vulnerable to ischemic damage; for instance, basal forebrain cholinergic nuclei are irrigated by penetrating arterioles susceptible to the effects of arterial hypertensionHippocampal CA1 neurons are particularly vulnerable to experimental ischemia, and hippocampal atrophy is common in patients with VaD in the absence of AD.


The safety and efficacy of donepezil have been studied in the largest clinical trial of pure VaD to date. A total of 1219 subjects were recruited for a 24-week, randomized, placebo-controlled, multicenter, multinational study divided into 2 identical trials, 307 and 308. The patients were randomized to 1 of 3 groups: placebo, donepezil 5 mg/d, or donepezil 10 mg/d. Most patients (73%) fulfilled diagnosis of probable VaD according to the NINDS-AIREN criteria. All had brain imaging before enrollment (CT or MRI) with demonstration of cerebrovascular lesions. Patients with preexisting AD and those with mixed dementia (AD plus CVD) were excluded.

The safety and efficacy of donepezil have been studied in the largest clinical trial of pure VaD to date. A total of 1219 subjects were recruited for a 24-week, randomized, placebo-controlled, multicenter, multinational study divided into 2 identical trials, 307 and 308. The patients were randomized to 1 of 3 groups: placebo, donepezil 5 mg/d, or donepezil 10 mg/d. Most patients (73%) fulfilled diagnosis of probable VaD according to the NINDS-AIREN criteria. All had brain imaging before enrollment (CT or MRI) with demonstration of cerebrovascular lesions. Patients with preexisting AD and those with mixed dementia (AD plus CVD) were excluded.

Donepezil (Aricept®)Donepezil (Aricept®)


Donepezil treatment group showed statistically significant improvement in cognitive functioning measured with the ADAS-cog; the mean changes from baseline score were as follows:

Donepezil 5 mg/d, -1.90 (P =0.001)

Donepezil 10 mg/d, -2.33 (P <0.001).


Donepezil 5 mg/d, -1.90 (P =0.001)

Donepezil 10 mg/d, -2.33 (P <0.001).

Black S, Román GC, et al. Donepezil 307 Vascular Dementia Study Group.Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke. 2003; 34: 2323–2332

Study 307Study 307

The MMSE also showed statistically significant improvement versus placebo.

CDR-SB showed nonsignificant benefit in the 5-mg/d group but was significant in the 10-mg/d group (P =0.007).

ADL showed significant benefits in donepezil-treated patients over placebo with the use of the ADFACS in both treatment groups (P >0.02).

The MMSE also showed statistically significant improvement versus placebo.

CDR-SB showed nonsignificant benefit in the 5-mg/d group but was significant in the 10-mg/d group (P =0.007).

ADL showed significant benefits in donepezil-treated patients over placebo with the use of the ADFACS in both treatment groups (P >0.02).

Study 307Study 307

Black S, Román GC, et al. Donepezil 307 Vascular Dementia Study Group.Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke. 2003; 34: 2323–2332


Donepezil 5 mg/d, -1.65 (P =0.003) Donepezil 10 mg/d, -2.09 (P =0.0002). The MMSE also showed statistically significant improvement versus placebo.


Donepezil 5 mg/d, -1.65 (P =0.003) Donepezil 10 mg/d, -2.09 (P =0.0002). The MMSE also showed statistically significant improvement versus placebo.

Wilkinson D, Doody R, et al. Donepezil 308 Study Group. Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology. 2003; 61: 479–486

Study 308Study 308

Study 308Study 308

CDR-SB showed non-significant benefit in the 5-mg/d group but was significant in the 10-mg/d group (P =0.03). ADL showed superiority in the donepezil-treated patients over placebo with the use of the ADFACS in both treatment groups, which, however, did not reach significance at the end of the study compared with placebo.

CDR-SB showed non-significant benefit in the 5-mg/d group but was significant in the 10-mg/d group (P =0.03). ADL showed superiority in the donepezil-treated patients over placebo with the use of the ADFACS in both treatment groups, which, however, did not reach significance at the end of the study compared with placebo.

Wilkinson D, Doody R, et al. Donepezil 308 Study Group. Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology. 2003; 61: 479–486

In a randomized controlled clinical trial, patients diagnosed with probable VaD or with AD combined with CVD received galantamine 24 mg/d (n=396) or placebo (n=196) in a multicenter, double-blind, 6-month trial. Eligible patients met the clinical criteria of probable VaD by NINDS-AIREN criteria . They also showed significant radiological evidence of CVD on CT or MRI.Evidence of CVD on a recent (within 12 months) scan included multiple large-vessel infarcts or a single, strategically placed infarct (angular gyrus, thalamus, basal forebrain, territory of the posterior or anterior cerebral artery), or at least 2 basal ganglia and white matter lacunae, or white matter changes involving at least 25% of the total white matter. The MMSE score was 10 to 25, ADAS-cog/11 score was >=12Age ranged from 40 to 90 years.

In a randomized controlled clinical trial, patients diagnosed with probable VaD or with AD combined with CVD received galantamine 24 mg/d (n=396) or placebo (n=196) in a multicenter, double-blind, 6-month trial. Eligible patients met the clinical criteria of probable VaD by NINDS-AIREN criteria . They also showed significant radiological evidence of CVD on CT or MRI.Evidence of CVD on a recent (within 12 months) scan included multiple large-vessel infarcts or a single, strategically placed infarct (angular gyrus, thalamus, basal forebrain, territory of the posterior or anterior cerebral artery), or at least 2 basal ganglia and white matter lacunae, or white matter changes involving at least 25% of the total white matter. The MMSE score was 10 to 25, ADAS-cog/11 score was >=12Age ranged from 40 to 90 years.

Erkinjuntti T, et al.. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002; 359: 1283–1290

Galantamine (Reminyl®)Galantamine (Reminyl®)

In analyses of both groups as a whole, galantamine demonstrated efficacy on all outcome measures. Galantamine showed greater efficacy than placebo on ADAS-cog (2.7 points; P <=0.001) and CIBIC-plus (74% versus 59% of patients remained stable or improved; P <=0.001). ADL and behavioral symptoms were also significantly improved compared with placebo (both P <0.05). Galantamine was well tolerated.

In an open-label extension, the original galantamine group of patients with probable VaD or AD plus CVD showed similar sustained benefits in terms of maintenance of or improvement in cognition (ADS-cog), functional ability (DAD), and behavior (NPI) after 12 months.

Although not designed to detect differences between subgroups, the subgroup of patients with AD plus CVD on galantamine (n=188; 48%) showed greater efficacy than placebo

In analyses of both groups as a whole, galantamine demonstrated efficacy on all outcome measures. Galantamine showed greater efficacy than placebo on ADAS-cog (2.7 points; P <=0.001) and CIBIC-plus (74% versus 59% of patients remained stable or improved; P <=0.001). ADL and behavioral symptoms were also significantly improved compared with placebo (both P <0.05). Galantamine was well tolerated.

In an open-label extension, the original galantamine group of patients with probable VaD or AD plus CVD showed similar sustained benefits in terms of maintenance of or improvement in cognition (ADS-cog), functional ability (DAD), and behavior (NPI) after 12 months.

Although not designed to detect differences between subgroups, the subgroup of patients with AD plus CVD on galantamine (n=188; 48%) showed greater efficacy than placebo

Erkinjuntti T, et al.. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002; 359: 1283–1290

Galantamine (Reminyl®)Galantamine (Reminyl®)

Rivastigmine: (Exelon®)Rivastigmine: (Exelon®)

Effectively inhibits acetylcholinesterase and butyrylcholinesterase (BuChE)

Clinical significance of BuChE is unknown

Reduces degradation rate of released acetylcholine, allowing more to be available for the postsynaptic receptor

Effectively inhibits acetylcholinesterase and butyrylcholinesterase (BuChE)

Clinical significance of BuChE is unknown

Reduces degradation rate of released acetylcholine, allowing more to be available for the postsynaptic receptor

Rivastigmine in VaDRivastigmine in VaDIn a small open-label study of patients with subcortical VaD, rivastigmine improved:

Caregiver stress

Activities of daily living

Behavior

Cognition

Demonstrated long-term efficacy

Clear dose response that can maximize efficacy

Needs efficacy assessment in larger, double-blind, randomized, placebo-controlled studies

In a small open-label study of patients with subcortical VaD, rivastigmine improved:

Caregiver stress

Activities of daily living

Behavior

Cognition

Demonstrated long-term efficacy

Clear dose response that can maximize efficacy

Needs efficacy assessment in larger, double-blind, randomized, placebo-controlled studies

Moretti R et al.. Rivastigmine in subcortical vascular dementia: an open 22-month study. J Neurol Sci. 2002; 203: 141–146

Memantine (Namenda®)Memantine (Namenda®)

Memantine after years of use in Europe is now approved by FDA in the US for use in mild to moderate Alzheimer,s disease.Drug that works differently from currently available anti-cholinesterase inhibitors. It is suggested that an overstimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate contributes to neurodegenerative disorders. Memantine blocks the overstimulation of the glutamate by blocking NMDA receptor

Memantine after years of use in Europe is now approved by FDA in the US for use in mild to moderate Alzheimer,s disease.Drug that works differently from currently available anti-cholinesterase inhibitors. It is suggested that an overstimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate contributes to neurodegenerative disorders. Memantine blocks the overstimulation of the glutamate by blocking NMDA receptor

Two randomized, placebo-controlled 6-month trials (MMM 300/MMM 500) studied memantine (20 mg/d) in mild to moderate probable VaD by NINDS-AIREN criteria.

Two randomized, placebo-controlled 6-month trials (MMM 300/MMM 500) studied memantine (20 mg/d) in mild to moderate probable VaD by NINDS-AIREN criteria.


In the MMM 300 study, 147 patients were randomized to memantine and 141 to placebo. After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo: the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score declined by 1.6, ie, a difference of 2.0 points (P =0.0016).

In the MMM 300 study, 147 patients were randomized to memantine and 141 to placebo. After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo: the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score declined by 1.6, ie, a difference of 2.0 points (P =0.0016).

Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia Internat Clin Psychopharmacol. 2002; 17: 297–305


MMM 300 studyMMM 300 study

The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo (P =0.227). The Gottfries-Bråne-Steen (GBS) Scale and the Nurses’ Observation Scale for Geriatric Patients (NOSGER) total scores at week 28 did not differ significantly between the 2 groups. GBS Scale intellectual function subscore and the NOSGER disturbing behavior dimension also showed a difference favoring memantine (P =0.04 and P =0.07, respectively).

The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo (P =0.227). The Gottfries-Bråne-Steen (GBS) Scale and the Nurses’ Observation Scale for Geriatric Patients (NOSGER) total scores at week 28 did not differ significantly between the 2 groups. GBS Scale intellectual function subscore and the NOSGER disturbing behavior dimension also showed a difference favoring memantine (P =0.04 and P =0.07, respectively).

Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia Internat Clin Psychopharmacol. 2002; 17: 297–305

MMM 500 studyMMM 500 study

The MMM 500 study randomized 277 patients to memantine and 271 to placebo. At 28 weeks, the active group had gained 0.53 points and the placebo group declined by 2.28 points in ADAS-cog, a significant difference of 1.75 ADAS-cog points between the groups (P <0.05). There were no differences in CGIC, Mini–Mental State Examination (MMSE), GBS, or NOSGER scores between groups. Memantine was well tolerated in both studies. In a post hoc pooled subgroup analysis of these 2 studies by baseline severity as assessed by MMSE, the more advanced patients obtained a larger cognitive benefit than did mildly affected patients. Patients with MMSE score <15 at baseline showed an ADAS-cog improvement of 3.2 points over placebo.

The MMM 500 study randomized 277 patients to memantine and 271 to placebo. At 28 weeks, the active group had gained 0.53 points and the placebo group declined by 2.28 points in ADAS-cog, a significant difference of 1.75 ADAS-cog points between the groups (P <0.05). There were no differences in CGIC, Mini–Mental State Examination (MMSE), GBS, or NOSGER scores between groups. Memantine was well tolerated in both studies. In a post hoc pooled subgroup analysis of these 2 studies by baseline severity as assessed by MMSE, the more advanced patients obtained a larger cognitive benefit than did mildly affected patients. Patients with MMSE score <15 at baseline showed an ADAS-cog improvement of 3.2 points over placebo.

Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Internat Clin Psychopharmacol. 2002; 17: 297–305

Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Internat Clin Psychopharmacol. 2002; 17: 297–305

Conclusions Conclusions

Vascular Dementia is a preventable disease

Progress has been made in the diagnosis and treatment of this condition

A public health approach should guide future research

Vascular Dementia is a preventable disease

Progress has been made in the diagnosis and treatment of this condition

A public health approach should guide future research

Vasc Demlecture

Health & Medicine

Transcript of Vasc Demlecture